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CRISPR genome editing treatment shows promise for genetic disorder

5 July 2021
Appeared in BioNews 1102

In-body CRISPR/Cas9 genome editing could offer an effective treatment for a rare, life-threatening genetic condition.

Interim results from an ongoing phase 1 clinical trial show that genome editing can be used to reduce the production of a toxic protein in patients with hereditary transthyretin (ATTR) amyloidosis.

'The data are extremely encouraging,' said trial leader Professor Julian Gillmore, head of the National Amyloidosis Centre at University College London. 'Until very recently, the majority of treatments we have been able to offer patients with this condition have had limited success. If this trial continues to go well, it will mean we can offer real hope and the prospect of meaningful clinical improvement to patients who suffer from this condition.'

People with ATTR amyloidosis have a mutation in the transthyretin (TTR) gene and produce a misfolded TTR protein that accumulates in tissues. The progressive condition causes numbness in the hands and feet, immobility, and is ultimately fatal.

The trial – whose results were published in The New England Journal of Medicine – has so far enrolled patients in London and New Zealand to evaluate the genome-editing-based therapy. The treatment aims to directly target and inactivate the TTR gene in liver cells to prevent the production of misfolded TTR protein.

Six patients with ATTR amyloidosis between the ages of 46 and 64 received a one-off intravenous infusion of the CRISPR/Cas9 construct. Twenty-eight days after treatment, three patients given the higher of two doses had reduced TTR levels by an average of 87 percent, with one patient having a 96 percent reduction. Furthermore, no serious adverse events were observed.

By contrast, the RNA-based drugs Patisiran (see BioNews 1006) and Inotersen, the standard-of-care for the condition, require routine administration and yield a reduction of about 80 percent.

'It could be potentially the first curative treatment for this hereditary disabling and life-threatening disease,' Professor David Adams, a neurologist at Paris-Saclay University in France, who led trials for Patisiran told Science.

As the trial progresses, patients will be given higher doses of the therapy in the hope of further lowering TTR levels. Researchers will also need to evaluate how effective the therapy is at targeting symptoms in a larger cohort of patients, as well as its long-term safety.

'This is a major milestone for patients,' said Professor Jennifer Doudna, Nobel Prize winner for her role in developing CRISPR genome editing, whose company Intellia Therapeutics part-funded the trial told NPR. 'While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place.'

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